tbuckley/cabot-search huggingface dataset:
OTHR-41. Amplification of the PLAG family genes – PLAGL1 and PLAGL2 – is a key feature of a novel embryonal CNS tumor type
Authors: Michaela-Kristina Keck, Martin Sill, Andrea Wittmann, Piyush Joshi Kumar, Damian Stichel, Philipp Sievers, Annika K Wefers, Federico Roncaroli, James Hayden, Martin G McCabe, Mariëtte E G Kranendonk, Michal Zapotocky, Alexandre Vasiljevic, Ulrich Schüller, Dominik Sturm, Mirjam Blattner-Johnson, Andreas von Deimling, Andrey Korshunov, Felix Sahm, Arie Perry, David Solomon, Stefan Pfister, David T W Jones
Journal: Neuro-Oncology (2022)

Abstract Pediatric central nervous system (CNS) tumors differ substantially from their adult counterparts, are marked by considerable molecular and clinical heterogeneity, and diagnosis through histopathology alone can be challenging. Using DNA methylation-based CNS tumor classification in combination with copy number and RNAseq analysis, we identify a rare, novel pediatric CNS tumor type (n=32) which is characterized by focal high-level amplification and consecutive overexpression of one of the PLAG family genes – PLAGL1 or PLAGL2. It is epigenetically divergent from other known tumor types such as high-grade gliomas, medulloblastomas, embryonal tumors, or CNS sarcomas. The wide range of original histopathologic diagnosis rendered attests to their polyphenotypic nature in terms of morphology. We suggest that these tumors may arise from early to intermediate neural progenitor cells with some neuronal commitment. Using ChIPseq data, we show that both PLAGL1 and PLAGL2 act as transcription factors for: i) the oncogenic kinase RET, a potential drug target, that was overexpressed in our cohort; ii) components of the Wnt/β-Catenin pathway; iii) a set of imprinted genes, reported to regulate the imprinted gene network in mouse models, that was deregulated in the PLAGL-amplified tumors. Consequently, a 250-gene expression PLAGL-signature indicated dysregulation of imprinting control and differentiation/development as a prominent feature. We report differences regarding age and sex distribution between PLAGL1- and PLAGL2-amplified tumors and shed light on differences in clinical behavior and outcomes between these subtypes in male and female patients. PLAGL1-amplified tumors were more prevalent in school-age children and teenagers, while PLAGL2-amplified cases occurred in very young patients. Kaplan-Meier analysis showed a trend towards a more favorable outcome in patients with PLAGL1-amplified tumors and in female patients. Survival rates remained constant after 5 years with a five-/ten-year overall survival of 75% for PLAGL1, 24% for PLAGL2, 18% for male patients, and 88% for female patients.
Towards advanced cardiac miRNA therapies through DNA-based nanostructures
Authors: N Hernandez-Bellido, A Postigo, C Orrite, E Garrido-Huescar, L Garcia-Mendivil, E Pueyo, S Hernandez-Ainsa, L Ordovas
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Proyecto MINECO-Ministerio de Ciencia e Innovación (Spain)- PID2019-105674RB-I00 Proyecto DGA- Diputación General de Aragón (Spain)- LMP128_21 Introduction Cardiac microRNAs (miRNAs) have been found to be dysregulated in cardiac disease and aging both in animal models and humans. Thanks to their pleiotropic effects, miRNAs are spotlighted as promising therapeutic targets to treat cardiac conditions. However, their low stability and potential off-target effects in vivo difficult the development of effective and safe miRNA therapies. Nanotechnology enables the fabrication of biocompatible carriers to perform targeted delivery of both conventional and advanced therapies. In particular, nanostructures built with DNA (DNS) have been successfully developed for miRNA therapies in cancer, but they have not been applied in cardiac therapy yet [1]. Purpose The main goal of this study is to demonstrate the capacity of DNS to deliver miRNA therapies in human cardiomyocytes. Methods Our group has identified MIR24-2 upregulated with age in the human left ventricle and miR24-2-5p to interact with genes related with the cardiac function, such as SERCA2 [2]. Different versions of DNS were designed and generated by self-assembly of DNA strands containing anti-miR24-2-5p capture segments. Physicochemical characterization of DNS was then conducted to determine their auto-assembling capacity, size, morphology and thermal stability. The characterization of the biological effect of the DNS was also conducted in vitro and in cell culture of HEK293 and human induced pluripotent stem cells (iPSC)-derived cardiomyocytes (iCM) to assess their cytotoxicity and internalization capacity. Results DNS were assembled correctly and reproducibly into carriers of around 30-50 nm. In vitro, the DNS showed thermal stability at physiological temperature, proper stability in serum and they disassembled specifically in the presence of the target miR24-2-5p sequence. In HEK293 and iCM cultures, the DNS showed lack of cytotoxicity demonstrating in vitro biocompatibility. DNS were efficiently internalized by HEK293, but the uptake capacity of DNS by iCM was remarkably lower. Conclusions We created and characterized biocompatible anti-miR-loaded DNS that effectively captured the target miR-24-2-5p in vitro. DNS internalized in iCM, but with lower efficiency than in HEK293 cells. Our results indicate that DNS are suitable candidates to carry miRNA therapies to human cardiac cells in vitro, but the observed cell-type specific differences suggest that future efforts need to be directed towards developing DNS functionalization capable of promoting efficient and specific carrier uptake in vivo by primary cardiac cells in vivo.
A Novel Targeted Nanoparticle for Traumatic Brain Injury Treatment: Combined Effect of ROS Depletion and Calcium Overload Inhibition (Adv. Healthcare Mater. 11/2022)
Authors: Zhengzhong Han, Yuhan Han, Xuyang Huang, Hongwei Ma, Xuefeng Zhang, Jingyuan Song, Jun Dong, Shanshan Li, Rutong Yu, Hongmei Liu
Journal: Advanced Healthcare Materials (2022)

Targeted Drug Delivery As shown in the cover picture, after brain injury, two groups of engineers (representing Np and PPS) are quickly sent to the injury area under the targeted transportation of a vehicle (CL-PPS/Np), to effectively prevent brain injury by blocking Ca2+ influx and decreasing ROS level through the combination of the properties of Np and PPS. This work is found in article number 2102256 by Shanshan Li, Rutong Yu, Hongmei Liu, and co-workers.
Emotional contagion and prosocial behavior in rodents
Authors: Christian Keysers, Ewelina Knapska, Marta A. Moita, Valeria Gazzola
Journal: Trends in Cognitive Sciences (2022)

Empathy is critical to adjusting our behavior to the state of others. The past decade dramatically deepened our understanding of the biological origin of this capacity. We now understand that rodents robustly show emotional contagion for the distress of others via neural structures homologous to those involved in human empathy. Their propensity to approach others in distress strengthens this effect. Although rodents can also learn to favor behaviors that benefit others via structures overlapping with those of emotional contagion, they do so less reliably and more selectively. Together, this suggests evolution selected mechanisms for emotional contagion to prepare animals for dangers by using others as sentinels. Such shared emotions additionally can, under certain circumstances, promote prosocial behavior.
Fully synthetic Tn-based three-component cancer vaccine using covalently linked TLR4 ligand MPLA and iNKT cell agonist KRN-7000 as built-in adjuvant effectively protects mice from tumor development
Authors: Deying Yang, Xiang Luo, Qinghai Lian, Lingqiang Gao, Chengxin Wang, Xiaoxiao Qi, Rong Zhang, Zhongqiu Liu, Guochao Liao
Journal: Acta Pharmaceutica Sinica B (2022)

We present a new strategy for self-adjuvanting vaccine development that has different types of covalently-linked immunostimulants as the carrier molecule. Using Tn antigen as the model, a three-component vaccine (MPLA-Tn-KRN7000) containing the TLR4 ligand MPLA and the iNKT cell agonist KRN7000 was designed and synthesized. This expands fully synthetic self-adjuvanting vaccine studies that use a single carrier to one with two different types of carriers. The corresponding two-component conjugate vaccines Tn-MPLA, Tn-KRN7000 and Tn-CRM197 were also synthesized, as controls. The immunological evaluation found that MPLA-Tn-KRN7000 elicits robust Tn-specific and T cell-dependent immunity. The antibodies specifically recognized, bound to and exhibited complement-dependent cytotoxicity against Tn-positive cancer cells. In addition, MPLA-Tn-KRN7000 increased the survival rate and survival time of tumor-challenged mice, and surviving mice reject further tumor attacks without any additional treatment. Compared to the glycoprotein vaccine Tn-CRM197, the two-component conjugate vaccines, Tn-MPLA and Tn-KRN7000, and the physical mixture of Tn-MPLA and Tn-KRN7000, MPLA-Tn-KRN7000 showed the most effect at combating tumor cells both in vitro and in vivo. The comparison of immunological studies in wild-type and TLR4 knockout mice, along with the test of binding affinity to CD1d protein suggests that the covalently linked MPLA-KRN7000 immunostimulant induces a synergistic activation of TLR4 and iNKT cell that improves the immunogenicity of Tn. This work demonstrates that MPLA-Tn-KRN7000 has the potential to be a vaccine candidate and provides a new direction for fully synthetic vaccine design.
LINC-13. Subependymal giant cell astrocytoma in a child with tuberous sclerosis complex: a case report
Authors: Citra Estetika, Ludi Dhyani Rahmartani, Amanda Soebadi, Kevin Gunawan, Eka Susanto, Muhammad Yanuar Amal
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION: Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder causing the formation of hamartomas in many organs, including the brain. It is generally benign but can block the flow of cerebrospinal fluid that increases intracranial pressure and leads to severe neurologic and behavioural changes. Subependymal giant cell astrocytoma (SEGA) occurs in 10-15% of TSC patients. Routine brain surveillance is important to look for SEGA in all TSC patients. CASE: We report a girl who was previously diagnosed with TSC at the age of two. She had hypomelanotic macules, facial angiofibroma, and a shagreen patch. Her first brain magnetic resonance imaging (MRI) was normal. She had routine consultation until she complained of recurrent headaches, walking instability, and seizures six years later. Her brain MRI showed a solid heterogenous intraventricular mass suggestive SEGA, with multiple subcortical hyperintense lesions (subcortical tubers), and hydrocephalus. She underwent emergency ventriculoperitoneal shunt (VP shunt) and tumor removal surgery. The histopathology examination matches SEGA, World health organization (WHO) grade I. It consists of polygonal to spindle cells with abundant eosinophilic cytoplasm. There are also large to multinucleated cells. After surgery, she had significant clinical improvement, and the seizure was controlled with valproic acid. CONCLUSION: It is essential to do brain evaluation using brain scan or MRI every 1-3 years as surveillance recommendation in all TSC patients. Early detection dramatically increases the chance of giving early treatment or surgery to lower complications and provide better outcomes. Keywords: Subependymal giant cell astrocytoma, tuberous sclerosis complex, surveillance, early diagnosis
OTHR-37. Pediatrics Cutaneous Reactions in Patient Treated with the Mitogen-Activated Protein Kinase Extracellular Signal-Regulated Kinase Inhibitor Trametinib
Authors: Mirit Gluck, Dan Ben-amitai, Rivka Friedland, Helen Toledano
Journal: Neuro-Oncology (2022)

Abstract OBJECTIVE: To describe the cutaneous adverse effects (AE) to MAPK Extracellular Signal-Regulated Kinase (MEK) Inhibitor Trametinib in the pediatric population. METHODS: This was a retrospective single-center study. Included were all pediatric patients, treated with trametinib, for an oncologic indication. All patients were evaluated by a pediatric dermatologist, prior to, and during treatment, with documentation of cutaneous findings. RESULT: Twenty patients were enrolled in the study. All patients received treatment with trametinib, of which 6 received a combination of trametinib and dabrafenib (BRAF inhibitor). Out of twenty patients, 18 patients (90%) presented with at least one cutaneous AE. Xerosis and pruritic eczematous changes were the most common (15 patients, 75%), which, in most cases, were tolerable and responded well to the use of emollients and topical corticosteroids. Eleven patients (55%) presented with paronychia which was treated with topical combined corticosteroids antifungals and antibiotics, all with good response. Six patients (30%) presented with acneiform eruption, treated with topical antibiotic, benzoyl peroxide and tretinoin, mostly with good response. Six patients (30%) presented with irreversible hair heterochromia. Reaction grades were reported for cutaneous reactions, most of them were Grade I or II. Only 2 patients reported to have grade III and IV cutaneous reactions: exfoliative dermatitis and erythema multiforme, respectively. Out of 6 patients that received combined treatment of trametinib and dabrafenib one patient had no cutaneous adverse reaction, and one had panniculitis (which was related to dabrafenib). The rest presented relatively mild AE. DISCUSSION: Cutaneous AEs are very common in children and adolescents treated with trametinib, and in most cases are classified as mild. Nevertheless, as this treatment is usually chronic, it is important to inform the patients and their guardians of the potential cutaneous toxicities prior to treatment initiation, and to refer them to a dermatologist for proper management.
Association of Thromboxane Generation With Survival in Aspirin Users and Nonusers
Authors: Jeffrey J. Rade, Bruce A. Barton, Ramachandran S. Vasan, Shari S. Kronsberg, Vanessa Xanthakis, John F. Keaney, Naomi M. Hamburg, Nikolaos Kakouros, Thomas A. Kickler
Journal: Journal of the American College of Cardiology (2022)
A phase II study of stereotactic body radiotherapy (SBRT) combined with sintilimab in patients with recurrent or oligometastatic hepatocellular carcinoma (HCC).
Authors: Yixing Chen, Ping Yang, Shisuo Du, Jian Zhou, Cheng Huang, Wenchao Zhu, Yong Hu, Yiyi Yu, Tianshu Liu, Zhaochong Zeng
Journal: Journal of Clinical Oncology (2022)

4071 Background: SBRT is an emerging treatment option for oligometastatic cancer disease. Preclinical studies have shown the synergistic effects between the radiotherapy and immunotherapy. Early clinical data also suggested that immunotherapy might augment the local effects of radiotherapy and decrease metastatic recurrence. This study aimed to evaluate the efficacy and safety of SBRT combined with sintilimab (a PD-1 antibody) in patients with recurrent or oligometastatic HCC. Methods: In this single arm, phase II study (NCT03857815), eligibility criteria included Pts with recurrent or oligometastatic HCC (defined as ≤5 metastatic/recurrent lesions), Child-Pugh class A, ECOG PS ≤ 1. Pts received sintilimab 200 mg IV Q3W for up to 12 months, progressive disease, unacceptable toxicity, or withdrawal. SBRT to all lesions was started at cycle 1 day 1. Primary endpoint was progression free survival (PFS) per RECIST 1.1. Secondary endpoints included safety, objective response rate (ORR), disease control rate (DCR) and overall survival (OS). Results: At data cutoff (Dec 28 th , 2021), 25 pts with 32 lesions were treated with SBRT + Sintilimab. SBRT was delivered at a median dose of 54 Gy (range 48-60) in 6 fractions (range 6-10) and the median follow-up time was 16.9 months (range 3.9-32.1). In those 25 evaluable pts, median age was 64 years (range 37-77), 24 (96%) were male, 24 (96%) were HBV+, 6 (24%) had extrahepatic metastasis, most pts had prior ≥2 local therapies. The confirmed ORR was 96% (24/25) according to RECIST 1.1 with 18pts CR and 6pts PR. 6-mo and 12-mo PFS rate was 100% and 70% (95%CI, 52.3%-93.6%), respectively.12-mo local control rate was 100%. Median PFS and OS was still not mature. Treatment-related adverse events (TRAEs) occurred in 14 pts (56%). Most common TRAEs were rash (16%), platelet count decreased (12%), myositis (8%). Grade 3 TRAEs (myositis) occurred in 1pt (4%). There were no grade 4-5 TRAEs. TRAEs led to discontinuation in 6 pts (24%). SAE were myocarditis (1pt Grade1), viral hepatitis (1pt Grade 3, treatment-independent) and upper gastrointestinal haemorrhage (1pt Grade 3, PD related). Conclusions: The combination of SBRT with Sintilimab was tolerable and showed an encouraging ORR of 96% in pts with recurrent or oligometastatic HCC. Longer follow up is required to further evaluate the efficacy and safety. Clinical trial information: NCT03857815.
Pernio and early SARS-CoV-2 variants: natural history of a prospective cohort and the role of interferon
Authors: Ashley T. Ng, John J. Moon, Olivia R. Steidl, Hailey Bussan, Jennifer M. Tran, George Luong, Aman Nihal, Meaghan Kenfield, Justin Frere, Benjamin R. TenOever, Ana C. Costa da Silva, Jacqueline W. Mays, Edward W. Cowen, Beth A. Drolet, Anne Marie Singh, Lisa M. Arkin
Journal: British Journal of Dermatology (2022)

Cases of new-onset pernio and recurrences in our cohort align tightly with trends in mean 7-day COVID-19 positivity in Wisconsin and mean temperature in Madison, Wisconsin by month.
External validation of new risk groups of progression and death in patients with biochemical relapse after prostatectomy, proposed by the European Association of Urology
Authors: R. Sopeña Sutil, D. Vázquez-Martul, E. Peña Vallejo, C. Altez Fernandez, M. Hernandez Arroyo, G. Rollon Prieto, R. Santos Perez De La Blanca, V. Chantada Abal, A. Rodriguez Antolin
Journal: European Urology (2022)
HGG-55. An adolescent with a High-Grade Glioma: persuing a specific diagnosis
Authors: Inês Romão Luz, Olinda Rebelo, José Augusto Costa, Alice Carvalho
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Recognizing the value of molecular parameters provides evidence with repercussions on diseases classification. CLINICAL CASE: A thirteen-year-old girl was admitted in coma at the Intensive Care Unit due to a hemorrhagic stroke. CT revealed an expansive left frontal lobe lesion with perilesional edema and compression signs by an extensive hematoma. She underwent an emergency decompressive craniotomy for hematoma drainage, and the lesion was biopsied. The subsequent MRI showed a large heterogeneous mass with a cystic component. A first subtotal resection of the lesion was performed considering the language area. The histopathological examination showed tumor cells organized in perivascular pseudorosettes around the central hyalinized thickened blood vessel throughout the tumor, a pattern typically encountered in astroblastoma. Immunochemistry stains revealed a positive reactivity for GFAP, Olig2, and synaptophysin. The molecular study found a BRAFV600E mutation and homozygous CDKN2A e CDKN2B deletions; no TERT amplification, BCORL1, nor MN1 gene rearrangements were identified. She completed six weeks of radiotherapy without neurological signs/symptoms. A new surgical intervention was done 12 weeks later due to a slight increase of residual lesion. The rapid growth and the presence of viable tumor cells justified the therapy with irinotecan and bevacizumab, with mild adverse effects. One year after diagnosis, the adolescent is clinically well, without neurologic deficits and the MRI without evidence of residue or tumor recurrence. DISCUSSION: We began therapy based on morphological diagnosis. Complete resection and radiotherapy proved to be beneficial as in other high-grade gliomas, but the value of other therapies is still unknown. The BRAF gene variant would allow treatment with dabrafenib (in association with trametinib) or vemurafenib; however, she presents molecular findings associated with poor prognosis (CDKN2A deletion) that may impair the effectiveness of these therapies. According to the new WHO classification, the absence of MN1 alterations precludes the diagnosis of astroblastoma.
Enrollment disparities in non-Hodgkin lymphoma clinical trials.
Authors: Stephanie Boisclair, Jose David Sandoval-Sus, Jonathan E. Kolitz, Joanna Meehan Rhodes
Journal: Journal of Clinical Oncology (2022)

e18594 Background: Disparities in cancer clinical trials limit the real-world reproducibility of their results while remaining inapplicable to excluded patients (pts) like those living with chronic viral infections. Non-Hodgkin lymphoma (NHL) has an incidence distributed heterogeneously among races and is associated with chronic viral infections such as HIV, Hepatitis B (Hep B) and Hepatitis C (Hep C). Given these epidemiological characteristics, we assessed demographic representation in NHL clinical trials to identify areas for improvement. Methods: Clinicaltrials.gov was queried for NHL trials and specified for completed, interventional, phase 2, 3 &amp; 4 trials, with results and with recruitment in the US. Trials including malignancies other than NHL, with enrollment outside of the US or lacking reported demographics on clinicaltrials.gov or trial publications were excluded. SEER 21 and the 2020 US census were used to calculate incident cases for each specified subgroup. Enrollment fraction (EF) was defined as the number of trial enrollees divided by the estimated US cases in each subgroup. We compared EF between subgroups utilizing odds ratios (OR) with p-value &lt; 0.05 deemed significant. Results: Of 176 trials meeting criteria, 64 (36.4%) reported ethnicity and 79 (44.9%) reported race. EF of Black, Asian/Pacific Islander, American Indian and Hispanic (HSP) pts were significantly lower compared to White and non-HSP pts (Table). Racial minorities were less likely to be enrolled in relapsed/refractory trials (OR 0.31 - 0.57 p &lt; 0.008) compared to White pts but all were equally likely to be enrolled in front-line trials. HSP pts had a lower EF compared to non-HSP pts in both relapsed/refractory and front-line trials (OR 0.57, 0.46 p &lt; 0.0001). Black and HSP pts were also less likely to be enrolled in hematopoietic stem cell transplant (HSCT) trials (OR 0.27, 0.74, p &lt; 0.003). Women had a significantly lower EF compared to men (Table). 150 trials had inclusion/exclusion criteria specific for chronic viral infections: 141 (94%) excluded pts with HIV, 108 (72%) with chronic Hep B and 103 (69%) with Hep C. Conclusions: Our study demonstrates underrepresentation of not only women, but also of Black, Asian/Pacific Islanders, American Indian and HSP pts in NHL trials, especially in relapsing/refractory and HSCT trials. Moreover, pts living with chronic viral infections are systematically excluded by trial criteria. It is essential that trials reporting on safety, toxicity and efficacy represent the true patient population to limit ascertainment bias and improve external validity of results.[Table: see text]